The present invention relates to a composition and method for administration of a radiosensitizer to enhance radiation treatment as a part of cancer therapy.
Radiation treatment has become a conventional part of cancer therapy. One shortcoming to radiotherapy, however, is the destruction to normal, healthy tissue surrounding the tumor which occurs during treatment. Another shortcoming is that after cessation of treatment, recurrence of the tumor can and does occur. Recurrence of the tumor has been partly attributed to the presence of radioresistant hypoxic tumor cells, and the enhancement of radiation dose to damage the hypoxic tumor tissue is often necessary. However, to save normal, healthy tissue, a reduction in the total radiation dose would be desirable. Obviously, these two factors are contradictory. Therefore, the use of certain drugs and chemicals that preferentially sensitize hypoxic tumor cells to radiation, radiosensitizers, are employed.
Radiosensitizers are chemical agents that have the capacity to increase the lethal effects of radiation when administered in conjunction with radiation and there are a variety of radiosensitizers that act by more than one mechanism. One class of radiosensitizers that directly alter the macromolecular apparatus determining the radiosensitivity are halogenated pyrimidines. The halogenated pyrimidines include 5-chlorodeoxy-uridine (CudR), 5-bromodeoxyuridine (BudR) and 5-iododeoxy-uridine (IudR). These radiosensitizers are incorporated into the DNA in the tumor cell in place of thymine and render the cell more susceptible to inactivation by radiation.
In cancer radiotherapy, the usefulness of inducing an increase in radiosensitivity by selective incorporation of a halogenated pyrimidine is limited by several factors. First, the drug must be present for a period long enough to allow the cells to pass through at least one DNA synthesis cycle since halogenated pyrimidines are incorporated only in cells in the S phase. While tumor cells often multiply faster than normal tissues, the fact that certain tumors may have doubling times varying from days to weeks complicates the planning of therapy. Second, the degree of radiosensitization is directly related to the degree of thymidine substitution. Hence, only a prolonged infusion of the drug in free form will maximize its incorporation. Third, it is not only the extent of sensitization that is important, but rather the total number of cells that must be sensitized to obtain any significant effect on the tumor. Fourth, the rapid hepatic degradation and dehalogentaion must be overcome.
One approach to overcoming some of these limitations has been to encapsulate the halogenated pyrimidine in liposomes. However, these attempts have not been entirely satisfactory because the radiosensitizers tend to leak out of the liposomes rapidly and the liposomes have poor stability in serum.
Accordingly, it is an object of the invention to provide a composition and method for administration of a radiosensitizer for radiotherapy.
It is a further object of the invention to provide a method for achieving radiosensitization of a tumor with a single, weekly dose.
It is a further object of the invention to provide a composition which achieves a two-fold higher distribution of the radiosensitizer in the tumor tissue than in the normal, healthy tissue.
In one aspect, the invention includes a method for administering a radiosensitizer to a tumor. The method includes preparing liposomes comprised of (i) a vesicle-forming lipid; (ii) between 1-20 mole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer chain, and (iii) between 1-15 mole percent of a radiosensitizer derivatized with a lipid moiety linked to the radiosensitizer; and administering the liposomes to a tumor-bearing patient.
In one embodiment, the radiosensitizer is 5-iodo-2xe2x80x2deoxyuridine or 5-bromo-2xe2x80x2deoxyuridine.
In another embodiment, the lipid moiety is a fatty acid or a saturated fatty acid. In other embodiments, the lipid moiety is selected from lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid and lignoceric acid.
In a preferred embodiment, the radiosensitizer is 5-iodo-2xe2x80x2-deoxyuridine and the lipid moiety is palmitic acid.
The radiosensitizer is derivatized with a second lipid moiety, in another embodiment of the invention. For example, the radiosensitizer is 5-iodo-21-deoxyuridine and the lipid moieties are palmitic acid.
The hydrophilic polymer chain included in the lipid composition and derivatized to a lipid moiety, in one embodiment, is polyethyleneglycol.
In another aspect, the invention includes a method for preparing a liposome composition including a radiosensitizer, by mixing in a lipid solvent (i) a vesicle-forming lipid; (ii) between 1-20 mole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer chain, and (iii) between 1-15 mole percent of a radiosensitizer derivatized with a lipid moiety linked to the radiosensitizer; and adding an amount of a second solvent selected (i) to achieve a lipid solvent amount greater than 10 weight percent and less than about 50 weight percent and (ii) to obtain a liposome size less than that obtained at another lipid solvent amount, where the lipid solvent and the second solvent are miscible in the resulting hydration mixture.
In one embodiment, the lipid solvent is an alcohol, such as methanol, ethanol or butanol. The second solvent, in one embodiment, is water.
In another aspect, the invention includes a liposome composition for administration of a radiosensitizer. The composition includes liposomes comprised of (i) a vesicle-forming lipid; (ii) between 1-20 mole percent of a vesicle-forming lipid derivatized with a hydrophilic polymer chain, and (iii) between 1-15 mole percent of a radiosensitizer derivatized with a lipid moiety linked to the radiosensitizer. The composition is formed by (a) mixing components (i), (ii) and (iii) in a lipid solvent; and (b) adding a selected amount of a second solvent, said selected amount effective (i) to achieve a lipid solvent amount greater than 10 weight percent and less than about 50 weight percent and (ii) to obtain a liposome size smaller than that obtained a lipid solvent amount other than said selected amount, said lipid solvent and said second solvent being miscible at the selected amount of second solvent.
These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings.